1. Field of the Invention
The present invention relates to a pharmaceutical preparation comprising at least one receptor/binding protein and a biodegradable polymer, such as hyaluronic acid or a derivative thereof in combination with at least one ligand for the binding proteins.
Using the combination of carrier+receptor/binding protein+active peptide, a slow release preparation is obtained. Alternatively, the principles of the present invention are also useful in controlling abnormally increased production of growth factors, as by tumor growth. In this case, the carrier+receptor/binding protein acts as a selective resorption agent of growth factors.
Receptors are protein molecules that can bind hormones and growth factors, i.e., ligands. Each type of receptor is specific for its ligand. The function of the receptor is to convey external signals, e.g., hormonal signals to the target cell. In addition, the soluble forms of the receptors may have an inherent targeting function which is useful for selective delivery of drugs, such as to injured areas. New achievements in receptor research have made it possible to obtain large quantities of specific pure receptor protein, which makes the present invention possible. Some of the known receptors include insulin-like growth factor-1-receptor, insulin-like growth factor-2-receptor, insulin-receptor, platelet derived growth factor receptor, fibroblast growth factor receptor, colony stimulating factor receptor, transforming growth factor receptors, growth hormone receptor, parathyroid hormone receptor, calcitonin receptor, estrogen receptor, tumor necrosis factor receptor, insulin-like growth factor serum binding protein, erythropoietin receptor and corticosteroid binding globulin.
It is generally known that growth factors and hormones, both in animals and in humans, stimulate important cellular processes concerning cell division, growth, maturation, differentiation, and the like. In addition, healing and regenerative processes are also regulated by these factors. The growth factors/hormones comprise, for example, insulin-like growth factor-1 and -2, IGF-1, IGF-2, platelet derived growth factor, PDGF; epidermal growth factor, EGF; fibroblast growth factor, FGF; nerve growth factor, NGF; colony stimulating factor, CSF; transforming growth factor, TGF; tumor necrosis factor, TNF; calcitonin, CT; parathyroid hormone, PTH; growth hormone, GH; estrogens, bombesin, bone morphogenetic protein, BMP; insulin, erythropoietin and corticosteroids.
Insulin, estrogens, corticosteroids, CT and GH are all well known pharmaceutical agents in daily clinical practice. Research is intense concerning the other different previously mentioned growth factors and hormones. Results of various studies have shown that PDGF and IGF-1 potentiate wound healing, GH increases fracture healing, etc. Although most of these growth factors and hormones have interesting effects, clinical implications for many of them are yet to be found. The results as hitherto obtained indicate that the means of administration currently used restrict the use of the substances as drugs because of the short half-life of peptides, the potency and the potential toxicity of the substances.
2. Description of Related Art
A number of researchers have identified and/or prepared receptors for growth factors or hormones. A partial listing of articles describing these techniques is as follows:
Ullrich, "Insulin-like Growth Factor 1 Receptor cDNA Cloning", Methods Enzymol. 1991, 198 p. 17-26.
MacDonald et al., "A Single Receptor Binds both Insulin-like Growth Factor II and Mannose-6-phosphate", Science, 1988 239(4844), p. 1134-7.
Paul et al., "Baculovirus-directed Expression of the Human Insulin Receptor and an Insulin-binding Ectodomain", J. Biol Chem, 1990, 265(22), p. 13074-83.
Duan et al., "A Functional Soluble Extracellular Region of the Platelet-derived Growth Factor", J. Biol Chem 1991, 266(1), p. 413-8.
Kiefer et al., "The Molecular Biology of Heparan Sulfate Fibroblast Growth Factor Receptors", Ann NY Acad Sci, 1991 638, p. 167-76.
Perch et al., "A Truncated, Secreted Form of the Epidermal Growth Factor Receptor is Encoded by Alternatively Spliced Transcript in Normal Rat Tissue", Mol Cell Biol, 1990, 10 (6), p. 2973-82.
Vissavajjhala et al., "Purification and Characterization of the Recombinant Extracellular Domain of Human Nerve Growth Factor Receptor Expressed in a Baculovirus System", J. Biol Chem 1990, 265 (8), p.4746-52.
Rapoport et al., "Granulocyte-macrophage Colony-stimulating Factor (GM-CSF) and Granulocyte Colony-stimulating Factor (G-CSF) Receptor Biology, Signals Transduction and Neutrophil Activation", Blood Rev, 1992, 6(1), p. 43-57.
Wang et al., "Expression Cloning and Characterization of the TGF-beta Type III Receptor", Cell, 1991, 67 (4), p. 797-805.
Fuh et al., "Rational Design of Potent Antagonists of the Human Growth Hormone Receptor", Science, 1992 256, p. 1677.
Abou-Samra et al., "Expression Cloning of a Common Receptor for Parathyroid Hormone and Parathyroid Hormone-related Peptide from Rat Osteoblast-like Cells: A Single Receptor Stimulates Intracellular Accumulation of both cAMP and Inositol Trisphosphates addn Increases Intracellular Free Calcium", Proc Natl Acad Sci USA, 1992, 89(7), p. 2732-6.
Lin et al., "Expression Cloning of an Adenylate Cyclase-coupled Calcitonin Receptor", Science, 1991, 254(5034), p. 1022-4.
Brown et al., "Human Estrogen Receptor Forms Multiple Protein-DNA Complexes", J Biol Chem, 1990, 265 (19), p. 11238-43.
Himmler et al., "Molecular Cloning and Expression of Human and Rat Tumor Necrosis Factor Receptor Chain (p60) and its Soluble Derivative, Tumor Necrosis Factor-binding Protein", DNA Cell Biol, 1990, 9(10), p. 705-15.
Kiefer et al., "Molecular Cloning of a New Human Insulin-like Growth Factor Binding Protein", Biochem Biophys Res Commun, 1991, 176(1) p. 219-25.
Ghose-Dastidar et al., "Expression of Biologically Active Human Corticosteroid Binding Globulin by Insect Cells; Acquisition of Function Requires Glycosylation and Transport", Proc Natl Acad Sci USA, 1991 88 (5) p. 6408-12.